Toxic Probes of Axonopathy

描述（由申请人提供）：申请人打算在拟议的5年研究生涯奖励期结束时，提高他的知识和发展研究技能，进行独立的科学神经科学研究。他将广泛参与执行神经毒理学研究，也将参加研讨会，期刊俱乐部，科学会议和教学活动。本研究计划拟以神经毒性芳香-二酮为工具，研究巨近端神经丝状轴索病（giant proximal neurofibroous axonopathy， GPNA）的发病机制和生物标志物。用1,2-二乙酰苯（1,2- dab）处理的啮齿动物在前角细胞、前根和背根神经节中产生了GPNA，在较小程度上。前角细胞GPNA也见于肌萎缩性侧索硬化症患者的早期死后活检。目标是：A)了解机制并识别γ -二酮诱导的GPNA的生物标志物；B)提高知识和发展研究技能，以便能够独立进行神经毒理学研究。具体目标是：1)确定1,2,4-三乙酰苯（1,2,4- trab）和1,2,4,5-四乙基苯（1,2,4,5- teab）的神经毒性特性，这两种物质都是芳香γ -二酮1,2- dab的表亲；2)捕获、比较和对比与γ -二酮神经病变相关的蛋白质谱和基因表达谱（时间允许）；3)确定导致GPNA发育的分子途径。这些目标将通过结合功能（轴突转运）、形态和组学（蛋白质组学和基因组学）的方法来实现。

DESCRIPTION (provided by applicant): The applicant intends to enhance his knowledge and develop research skills to conduct independent scientific neuroscience-focused research at the end of the proposed 5-year research career award period. He will be extensively involved in performing neurotoxicological research and will also participate in seminars, journals clubs, scientific meetings and teaching activities. The research plan proposes to use neurotoxic aromatic gamma-diektones as tools to study mechanisms and biomarkers of giant proximal neurofilamentous axonopathy (GPNA). Rodents treated with 1,2-diacetylbenzene (1,2-DAB) develop GPNA in anterior horn cells, ventral roots and, to a lesser extend, in the dorsal root ganglia. Anterior horn cell GPNA is also seen in early post-mortem biopsies of subjects with amyotrophic lateral sclerosis. The objectives are: A) to understand mechanisms and identify biomarkers of gamma-diketone-induced GPNA to B) enhance knowledge and develop research skills to be able to conduct neurotoxicological research independently. Specific aims are: 1) to determine neurotoxic properties of 1,2,4-triacetylbenzene (1,2,4-TrAB) and 1,2,4,5-tetracetylbenzene (1,2,4,5-TeAB), both cousins of the aromatic gamma-diketone 1,2-DAB, 2) to capture, compare and contrast protein profiles and gene expression profiles (time permitting) associated with gamma-diketone neuropathy, and 3) to identify molecular pathways that lead to the development of GPNA. These goals will be reached using a combination of functional (axonal transport), morphologic and omics (proteomics and genomics) methodologies.